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Evaluation of drug interactions in the established FEC regimen in primary cultures of tumour cells from patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
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2000 (English)In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 11, no 10, 1301-1307 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Chemotherapy using multi-drug regimens is considered more active than single-agent therapy. This may be due to synergistic interactions or, simply, a higher probability of administering an active agent. We investigated in vitro the type of drug interactions in a recognized regimen in relationship to tumour type and drug sensitivity.

PATIENTS AND METHODS:

The possibility of synergistic and additive interactions between individual cytotoxic drugs was investigated for the component drugs of the established FEC regimen, i.e., 5-fluorouracil, epirubicin and cyclophosphamide, in 243 patient tumour samples representing various drug sensitivity using the non-clonogenic fluorometric microculture cytotoxicity assay.

RESULTS:

Using a cell survival of < or = 50% as a limit for drug activity and sample sensitivity, the overall response rates to the most active single drug (Dmax) and the combination were 56% and 64%, respectively, with a distribution among diagnoses similar to that in the clinic. For 86% of the samples there was concordance with respect to judgement of activity using either Dmax or the combination. For samples being sensitive to at least one single drug, 95% were also sensitive to the combination whereas for samples with insignificant Dmax effect, only 2% were sensitive to the combination. In samples with modest Dmax effects, i.e., cell survival in the range > 50%- < or = 80%, 45% responded to the combination. The effect of the combination was generally well predicted from the Dmax effect.

CONCLUSIONS:

The superior antitumour effect of drug combinations compared with single drugs may be due to the higher chance of selecting an active agent. However, for intermediately sensitive tumours, additional interaction effects of a combination may be of clinical significance.

Place, publisher, year, edition, pages
2000. Vol. 11, no 10, 1301-1307 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-57287PubMedID: 11106120OAI: oai:DiVA.org:uu-57287DiVA: diva2:85196
Available from: 2007-02-09 Created: 2007-02-09 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Exploring Cancer Drugs In Vitro and In Vivo: With Special Reference to Chemosensitivity Testing and Early Clinical Development
Open this publication in new window or tab >>Exploring Cancer Drugs In Vitro and In Vivo: With Special Reference to Chemosensitivity Testing and Early Clinical Development
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aims of this thesis were to investigate the utility of in vitro drug sensitivity testing to optimize the use of cancer chemotherapy and to assess the properties of a new cancer drug in a phase I clinical trial. Tumour cells from patients were analysed with the short-term Fluorometric Microculture Cytotoxicity Assay (FMCA). In samples from a wide spectrum of tumour types, the effect of the drug combination FEC (5Fu-epirubicin-cyclophosphamide) was generally appropriately predicted from the effect of the best component drug. However, of samples intermediately sensitive to the best single drug, 45% converted to sensitive when testing the combination. Thus, combination testing may identify advantageous interactions and improve in vitro test performance. In tumour samples from peritoneal carcinomatosis, significant differences in drug sensitivity between diagnoses were observed, cross-resistance between most drugs was modest or absent, and the concentration-effect relationships for two drugs in individual samples varied considerably. Thus, for optimal selection of drugs for intraperitoneal chemotherapy, differences in drug sensitivity at the diagnosis and individual patient level should be considered. In samples from patients with ovarian carcinoma, drug sensitivity was related to tumour grade, histologic subtype and patient treatment status. In a homogeneous subset of patients, the FMCA predicted individual patient tumour response with high sensitivity and specificity. Thus, if carefully interpreted in the context of important clinical variables, in vitro testing could be of value for individualizing chemotherapy in ovarian cancer. Employing a once weekly dosing schedule in a phase I trial, the mechanistically new and preclinically promising NAD depleting drug CHS 828 produced dose limiting thrombocytopenia and gastrointestinal toxicity without clear evidence of anti-tumour efficacy. It is concluded that in vitro drug sensitivity testing could be a way to optimize the use of chemotherapy and that successful development of new cancer drugs needs improved strategies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 675
Keyword
cytotoxic drug, in vitro assay, drug development, phase I clinical trial
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-151826 (URN)978-91-554-8087-5 (ISBN)
Public defence
2011-06-03, Auditorium Minus, Gustavianum, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-05-13 Created: 2011-04-18 Last updated: 2011-07-01Bibliographically approved

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von Heideman, ALarsson, R

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